The long term goals of this project are to understand how torsinA, the product of the DYT1 gene, regulates neurogenesis and neuronal migration in the developing brain. TorsinA is a member of the AAA+ superfamily of proteins that typically mediate conformational changes in protein complexes. The majority of TorsinA is localized within the endoplasmic reticulum and the contiguous nuclear envelope where it links the nuclear envelope with the cytoskeleton. In this location, torsinA is implicated in organelle movement, including nuclear translocation in dividing and migrating cells, suggesting a role for this protein in both neurogenesis and neuronal migration. The experiments proposed here will test the hypothesis that torsinA plays critical roles in GABA neuron migration and the development of the dopaminergic system in the cerebral cortex and basal ganglia of the developing brain. These two neurotransmitter systems and brain regions are implicated in the pathophysiology of early onset torsion dystonia (also called DYT1 dystonia), which is associated with mutations in the DYT1 gene. The experiments will use DYT1 knockout mice as well as DYT1 delGAG knock-in mice (the latter represent the DYT1 dystonia disease genotype) as loss or gain of function models. The data are expected to provide insights into the role of torsinA in brain development, at the cellular and systems level. Understanding the role of torsinA in CNS development is essential for correlating the biological functions of torsinA with pathogenesis of DYT1 dystonia, which is a developmental disorder. The disease process is not linked yet to specific cellular processes or molecular mechanisms in the developing brain. Therefore, constructing mechanistic models of the disease requires information on the role of torsinA in processes such as neuronal migration or neuronal differentiation in the developing brain. PUBLIC HEALTH RELEVANCE: Our research is relevant to public health because it examines the mechanisms by which the genetic mutation associated with the cause of early onset torsion dystonia (DYT1 dystonia) may impair development of brain regions and neurotransmitter systems underlying the control of movement.